Alzheimer disease (AD) is the most common form of dementia, with an estimated lifetime risk of nearly one in five for women and 1 in 10 for men. AD is highly heritable, even in so-called sporadic cases. The genetic basis for AD is best understood in the early-onset form, which accounts for less than one percent of cases and typically follows an autosomal dominant inheritance pattern related to mutations in genes that alter amyloid-beta (Aβ) protein production, aggregation, or clearance. The genetic basis of late-onset AD is more complex, with susceptibility likely conferred by a variety of more common but less penetrant genetic factors, such as apolipoprotein E (APOE) alleles, interacting with environmental and epigenetic influences.

The genetic contribution to Alzheimer disease (AD) risk remains poorly understood despite major advances in the 1990’s in the identification of three genes that cause early-onset familial AD and one genetic risk factor for late-onset AD (LOAD). There have been three main strategies employed to identify genetic factors that predispose to the development of AD: linkage analysis, candidate gene studies, and genome-wide association studies. General principles of genetic variation and genetic association studies are discussed separately. (See "Overview of genetic variation" and "Genetic association studies: Principles and applications".)

Linkage analysis — The first progress in understanding the genetic basis of AD resulted from studies of families displaying autosomal dominant inheritance of the disorder. These studies used linkage-based methodology, in which a relatively small number (on the order of several hundred) of non-functional genetic markers spaced throughout the genome are genotyped in order to determine whether a given section of chromosome was transmitted from parents to their offspring. By comparing this information to disease status, the genes responsible can be mapped to relatively large chromosomal regions. Early AD studies used linkage analysis to identify culprit regions on chromosomes 1, 14, and 21, eventually leading to discovery of the three known causative AD genes [1-4]. (See 'Early-onset Alzheimer Disease' below.)

Whereas linkage analysis has been very successful in identifying monogenic traits in early-onset familial AD, it has had much more limited success in late-onset AD, which is more likely to be a complex trait. (See 'Challenges' below.)

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